This project is focused on the characterization of HIV-1-specific cellular and humoral and humoral immunity in HIV-1 infected or immunized individuals and in a small animal model. The proposed study will continue to define HIV structural and non-structural proteins which are important for the generation of protective immune responses. Over the past four years we have made significant contributions to our understanding of HIV-1 specific cellular and humoral immune responses in children and adults. During the next project period we propose the following: 1. To continue to examine the role of HIV-1-specific CTL in the control of viral replication and disease progression. Studies will seek to define the role of Nef-specific CTL responses in individuals with long-term non- progressive infection, and the influence of broad, cross-clade responses on viral load and the rate of CD4 T cell loss. 2. To study primary and secondary human immune responses to HIV-1 in a novel NOD-scid mouse model and evaluate the correlates of protection from HIV-1 infection in this model. 3. To conduct a phase I clinical trial to examine safety and immunogenicity of recombinant vaccinia and fowl-pox vaccines expressing autologous HIV-1 gene products in vertically infected children treated with highly active anti-retroviral therapy (HAART). We have a established laboratory focused on the immunopathogenesis of HIV- 1 infection and we are poised to contribute further to our understanding of HIV-1 protective immune responses.